Atherosclerosis and its devastating clinical complications --- arterial thrombosis, ischemia and infarction of the heart, brain and other vital organs, ruptured aortic aneurysms and peripheral vascular insufficiency --- continue to account for the majority of the morbidity and mortality in the adult populations of industrialized nations. Despite major advances in our understanding of lipid metabolism and its role in promoting atheroma formation, much remains to be learned about the pathobiology of atherosclerosis, in particular, how systemic risk factors such as hypercholesteremia contribute to the progressive narrowing/remodeling, scarring/calcification, and lipid accumulation found at sites of atherosclerotic plaque formation. The primary focus of this competitive renewal SCOR Program continues to be atherogenesis, the pathogenetic sequence of events occurring within the arterial wall that leads to clinical disease. Our goal is to define the cellular and molecular mechanisms involved in certain critical transitions in the natural history of the atherosclerotic plaque , which underly its anatomical localization and temporal progression to an unstable/vulnerable stage predisposing to intravascular thrombosis. Project Aims include: (1) the discovery of endothelial genes induced by hemodynamic forces that contribute to, or protect against, localized lesion initiation; (2) testing in vivo the roles of matrix-degrading proteinases, and collagen destruction on plaque stability as critical determinants of endothelial durability and plaque stability; (3) exploring the functional importance of cell-mediated immune mechanisms in lesion progression/regression; (4) defining the role of the NF-kB/IkappaB transcription factor system in the regulation of expression of atherosclerosis-related genes in the vascular wall; (5) applying the emerging technologies of nuclear magnetic resonance imaging in animal models and human subjects, to define the "functional anatomy" of plaques, and to study the mechanisms by which lipid-lowering and other interventions affect plaque structure and stability. An interdisciplinary team of basic investigators and clinician-scientists, with expertise in vascular biology, cardiovascular pathology and medicine, and biornechanical engineering, has been assembled in a supportive institutional environment. These studies should yield new insights into the pathogenesis and effective therapeutic interventions for atherosclerotic cardiovascular disease.